tbuckley/cabot-search huggingface dataset:
Effects of boosting and waning in highly exposed populations on dengue epidemic dynamics
Authors: Rosemary A. Aogo, Jose Victor Zambrana, Nery Sanchez, Sergio Ojeda, Guillermina Kuan, Angel Balmaseda, Aubree Gordon, Eva Harris, Leah C. Katzelnick
Journal: Science Translational Medicine (2023)

Sequential infection with multiple dengue virus (DENV) serotypes is thought to induce enduring protection against dengue disease. However, long-term antibody waning has been observed after repeated DENV infection. Here, we provide evidence that highly immune Nicaraguan children and adults ( n = 4478) experience boosting and waning of antibodies during and after major Zika and dengue epidemics. We develop a susceptible-infected-recovered-susceptible (SIRS-type) model that tracks immunity by titer rather than number of infections to show that boosts in highly immune individuals can contribute to herd immunity, delaying their susceptibility to transmissible infection. In contrast, our model of lifelong immunity in highly immune individuals, as previously assumed, results in complete disease eradication after introduction. Periodic epidemics under this scenario can only be sustained with a constant influx of infected individuals into the population or a high basic reproductive number. We also find that Zika virus infection can boost DENV immunity and produce delays and then surges in dengue epidemics, as observed with real epidemiological data. This work provides insight into factors shaping periodicity in dengue incidence and may inform vaccine efforts to maintain population immunity.
Targeting DNA methylation and B7-H3 in RB1-deficient and neuroendocrine prostate cancer
Authors: Yasutaka Yamada, Varadha Balaji Venkadakrishnan, Kei Mizuno, Martin Bakht, Sheng-Yu Ku, Maria Mica Garcia, Himisha Beltran
Journal: Science Translational Medicine (2023)

Aberrant DNA methylation has been implicated as a key driver of prostate cancer lineage plasticity and histologic transformation to neuroendocrine prostate cancer (NEPC). DNA methyltransferases (DNMTs) are highly expressed, and global DNA methylation is dysregulated in NEPC. We identified that deletion of DNMT genes decreases expression of neuroendocrine lineage markers and substantially reduced NEPC tumor development and metastasis in vivo. Decitabine, a pan-DNMT inhibitor, attenuated tumor growth in NEPC patient–derived xenograft models, as well as retinoblastoma gene ( RB1 )–deficient castration-resistant prostate adenocarcinoma (CRPC) models compared with RB1 -proficient CRPC. We further found that DNMT inhibition increased expression of B7 homolog 3 (B7-H3), an emerging druggable target, via demethylation of B7-H3. We tested DS-7300a (i-DXd), an antibody-drug conjugate targeting B7-H3, alone and in combination with decitabine in models of advanced prostate cancer. There was potent single-agent antitumor activity of DS-7300a in both CRPC and NEPC bearing high expression of B7-H3. In B7-H3–low models, combination therapy of decitabine plus DS-7300a resulted in enhanced response. DNMT inhibition may therefore be a promising therapeutic target for NEPC and RB1-deficient CRPC and may sensitize B7-H3–low prostate cancer to DS-7300a through increasing target expression. NEPC and RB1-deficient CRPC represent prostate cancer subgroups with poor prognosis, and the development of biomarker-driven therapeutic strategies for these populations may ultimately help improve patient outcomes.
Parathyroid hormone treatment partially reverses endplate remodeling and attenuates low back pain in animal models of spine degeneration
Authors: Zemin Ling, Janet Crane, Hao Hu, Yan Chen, Mei Wan, Shuangfei Ni, Shadpour Demehri, Bahram Mohajer, Xinsheng Peng, Xuenong Zou, Xu Cao
Journal: Science Translational Medicine (2023)

Low back pain (LBP) is one of the most prevalent diseases affecting quality of life, with no disease-modifying therapy. During aging and spinal degeneration, the balance between the normal endplate (EP) bilayers of cartilage and bone shifts to more bone. The aged/degenerated bony EP has increased porosity because of osteoclastic remodeling activity and may be a source of LBP due to aberrant sensory innervation within the pores. We used two mouse models of spinal degeneration to show that parathyroid hormone (PTH) treatment induced osteogenesis and angiogenesis and reduced the porosity of bony EPs. PTH increased the cartilaginous volume and improved the mechanical properties of EPs, which was accompanied by a reduction of the inflammatory factors cyclooxygenase-2 and prostaglandin E 2 . PTH treatment furthermore partially reversed the innervation of porous EPs and reversed LBP-related behaviors. Conditional knockout of PTH 1 receptors in the nucleus pulposus (NP) did not abolish the treatment effects of PTH, suggesting that the NP is not the primary source of LBP in our mouse models. Last, we showed that aged rhesus macaques with spontaneous spinal degeneration also had decreased EP porosity and sensory innervation when treated with PTH, demonstrating a similar mechanism of PTH action on EP sclerosis between mice and macaques. In summary, our results suggest that PTH treatment could partially reverse EP restructuring during spinal regeneration and support further investigation into this potentially disease-modifying treatment strategy for LBP.
Impact of pain and adverse health outcomes on long-term US testicular cancer survivors
Authors: Paul C Dinh, Patrick O Monahan, Sophie D Fosså, Howard D Sesso, Darren R Feldman, M Eileen Dolan, Kathryn Nevel, John Kincaid, David J Vaughn, Neil E Martin, Victoria A Sanchez, Lawrence H Einhorn, Robert Frisina, Chunkit Fung, Kurt Kroenke, Lois B Travis
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background No study has quantified the impact of pain and other adverse health outcomes on global physical and mental health in long-term US testicular cancer survivors or evaluated patient-reported functional impairment due to pain. Methods Testicular cancer survivors given cisplatin-based chemotherapy completed validated surveys, including Patient-Reported Outcomes Measurement Information System v1.2 global physical and mental health, Patient-Reported Outcomes Measurement Information System pain questionnaires, and others. Multivariable linear regression examined relationships between 25 adverse health outcomes with global physical and mental health and pain-interference scores. Adverse health outcomes with a β^ of more than 2 are clinically important and reported below. Results Among 358 testicular cancer survivors (median age = 46 years, interquartile range [IQR] = 38–53 years; median time since chemotherapy = 10.7 years, IQR = 7.2–16.0 years), median adverse health outcomes number was 5 (IQR = 3–7). A total of 12% testicular cancer survivors had 10 or more adverse health outcomes, and 19% reported chemotherapy-induced neuropathic pain. Increasing adverse health outcome numbers were associated with decreases in physical and mental health (P &amp;lt; .0001 each). In multivariable analyses, chemotherapy-induced neuropathic pain (β^ = −3.72; P = .001), diabetes (β^ = −4.41; P = .037), obesity (β^ = −2.01; P = .036), and fatigue (β^ = −8.58; P &amp;lt; .0001) were associated with worse global mental health, while being married or living as married benefited global mental health (β^ = 3.63; P = .0006). Risk factors for pain-related functional impairment included lower extremity location (β^ = 2.15; P = .04) and concomitant peripheral artery disease (β^ = 4.68; P &amp;lt; .001). Global physical health score reductions were associated with diabetes (β^ = −3.81; P = .012), balance or equilibrium problems (β^ = −3.82; P = .003), cognitive dysfunction (β^ = −4.43; P &amp;lt; .0001), obesity (β^ = −3.09; P &amp;lt; .0001), peripheral neuropathy score (β^ = −2.12; P &amp;lt; .0001), and depression (β^ = −3.17; P &amp;lt; .0001). Conclusions Testicular cancer survivors suffer adverse health outcomes that negatively impact long-term global mental health, global physical health, and pain-related functional status. Clinically important factors associated with worse physical and mental health identify testicular cancer survivors requiring closer monitoring, counseling, and interventions. Chemotherapy-induced neuropathic pain must be addressed, given its detrimental impact on patient-reported functional status and mental health 10 or more years after treatment.
Transcriptome-based identification of tumor-reactive and bystander CD8 <sup>+</sup> T cell receptor clonotypes in human pancreatic cancer
Authors: Zibo Meng, Aaron Rodriguez Ehrenfried, Chin Leng Tan, Laura K. Steffens, Hannes Kehm, Stefan Zens, Claudia Lauenstein, Alina Paul, Marius Schwab, Jonas D. Förster, Mogjiborahman Salek, Angelika B. Riemer, Heshui Wu, Christoph Eckert, Carl-Stephan Leonhardt, Oliver Strobel, Michael Volkmar, Isabel Poschke, Rienk Offringa
Journal: Science Translational Medicine (2023)

Pancreatic ductal adenocarcinoma (PDAC) is generally refractory to immune checkpoint blockade, although patients with genetically unstable tumors can show modest therapeutic benefit. We previously demonstrated the presence of tumor-reactive CD8+ T cells in PDAC samples. Here, we charted the tumor-infiltrating T cell repertoire in PDAC by combining single-cell transcriptomics with functional testing of T cell receptors (TCRs) for reactivity against autologous tumor cells. On the basis of a comprehensive dataset including 93 tumor-reactive and 65 bystander TCR clonotypes, we delineated a gene signature that effectively distinguishes between these T cell subsets in PDAC, as well as in other tumor indications. This revealed a high frequency of tumor-reactive TCR clonotypes in three genetically unstable samples. In contrast, the T cell repertoire in six genetically stable PDAC tumors was largely dominated by bystander T cells. Nevertheless, multiple tumor-reactive TCRs were successfully identified in each of these samples, thereby providing a perspective for personalized immunotherapy in this treatment-resistant indication.
Long-term aspirin use and cancer risk: a 20-year cohort study
Authors: Charlotte Skriver, Thomas Maltesen, Christian Dehlendorff, Charlotte Wessel Skovlund, Morten Schmidt, Henrik Toft Sørensen, Søren Friis
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background Long-term use of aspirin has been shown to reduce colorectal cancer risk, but the association remains inconclusive for individual noncolorectal cancers. We examined the association between long-term aspirin use and cancer risk in Denmark. Methods Using nationwide registries, we followed individuals aged 40-70 years at baseline (January 1, 1997) for cancer diagnoses through 2018. We assessed low-dose (75-150 mg) aspirin use according to continuity, duration, and cumulative amount. In addition, we explored associations with consistent high-dose (500 mg) aspirin use. Using Cox regression, we estimated multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) with aspirin use for overall and site-specific cancer. Results Among 1 909 531 individuals, 422 778 were diagnosed with cancer during mean follow-up of 18.2 years. Low-dose aspirin use did not reduce the hazard ratio for cancer overall irrespective of continuity and duration of use (continuous use: HR = 1.04, 95% CI = 1.03 to 1.06). However, long-term (≥5 or ≥10 years) use was associated with at least 10% reductions in hazard ratios for several cancer sites: colon, rectum, esophagus, stomach, liver, pancreas, small intestine, head and neck, brain tumors, meningioma, melanoma, thyroid, non-Hodgkin lymphoma, and leukemia. Substantially elevated hazard ratios were found for lung and bladder cancer. In secondary analyses, consistent high-dose aspirin use was associated with reduced hazard ratios for cancer overall (HR = 0.89, 95% CI = 0.85 to 0.93) and for several cancer sites. Conclusion Long-term low-dose aspirin use was associated with slight to moderately reduced risks for several cancers but not for cancer overall owing to increased risk for some common cancers. Similar or slightly stronger inverse associations were observed for consistent use of high-dose aspirin.
Preclinical Characterization of AZD9574, a Blood–Brain Barrier Penetrant Inhibitor of PARP1
Authors: Anna D. Staniszewska, Domenic Pilger, Sonja J. Gill, Kunzah Jamal, Natacha Bohin, Sofia Guzzetti, Jacob Gordon, Gregory Hamm, Gill Mundin, Giuditta Illuzzi, Andy Pike, Lisa McWilliams, Gareth Maglennon, Jonathan Rose, Glen Hawthorne, Miguel Cortes Gonzalez, Christer Halldin, Peter Johnström, Magnus Schou, Susan E. Critchlow, Stephen Fawell, Jeffrey W. Johannes, Elisabetta Leo, Barry R. Davies, Sabina Cosulich, Jann N. Sarkaria, Mark J. O'Connor, Petra Hamerlik
Journal: Clinical Cancer Research (2023)

Abstract Purpose: We evaluated the properties and activity of AZD9574, a blood–brain barrier (BBB) penetrant selective inhibitor of PARP1, and assessed its efficacy and safety alone and in combination with temozolomide (TMZ) in preclinical models. Experimental Design: AZD9574 was interrogated in vitro for selectivity, PARylation inhibition, PARP-DNA trapping, the ability to cross the BBB, and the potential to inhibit cancer cell proliferation. In vivo efficacy was determined using subcutaneous as well as intracranial mouse xenograft models. Mouse, rat, and monkey were used to assess AZD9574 BBB penetration and rat models were used to evaluate potential hematotoxicity for AZD9574 monotherapy and the TMZ combination. Results: AZD9574 demonstrated PARP1-selectivity in fluorescence anisotropy, PARylation, and PARP-DNA trapping assays and in vivo experiments demonstrated BBB penetration. AZD9574 showed potent single agent efficacy in preclinical models with homologous recombination repair deficiency in vitro and in vivo. In an O6-methylguanine-DNA methyltransferase (MGMT)–methylated orthotopic glioma model, AZD9574 in combination with TMZ was superior in extending the survival of tumor-bearing mice compared with TMZ alone. Conclusions: The combination of three key features—PARP1 selectivity, PARP1 trapping profile, and high central nervous system penetration in a single molecule—supports the development of AZD9574 as the best-in-class PARP inhibitor for the treatment of primary and secondary brain tumors. As documented by in vitro and in vivo studies, AZD9574 shows robust anticancer efficacy as a single agent as well as in combination with TMZ. AZD9574 is currently in a phase I trial (NCT05417594). See related commentary by Lynce and Lin, p. 1217
SAR-096: Phase II Clinical Trial of Ribociclib in Combination with Everolimus in Advanced Dedifferentiated Liposarcoma (DDL) and Leiomyosarcoma (LMS)
Authors: Sujana Movva, Sahar Matloob, Elizabeth A. Handorf, Edwin Choy, Priscilla Merriam, Douglas B. Flieder, Kathy Q. Cai, Yan Zhou, Eric D. Tetzlaff, Cheyenne Pagan, Emma Barker, Rosanna Veggeberg, Delia Zumpano, Lori Rink, Margaret von Mehren, Suzanne George
Journal: Clinical Cancer Research (2023)

Dedifferentiated liposarcoma (DDL) and leiomyosarcoma (LMS) are two common subtypes of soft-tissue sarcoma, a rare group of diseases for which new treatments are needed. Chemotherapy remains the standard option for advanced disease. Targeting cyclin-dependent kinase 4 and 6 (CDK4/6) in DDL and mTOR in LMS is of biologic interest. When combined, the CDK4 inhibitor ribociclib and the mTOR inhibitor everolimus have shown synergistic growth inhibition in multiple tumor models, suggesting that this combination could be beneficial in patients.
Detection of Recurrence through microRNA-371a-3p Serum Levels in a Follow-up of Stage I Testicular Germ Cell Tumors in the DRKS-00019223 Study
Authors: Gazanfer Belge, Cansu Dumlupinar, Tim Nestler, Markus Klemke, Peter Törzsök, Emanuela Trenti, Renate Pichler, Wolfgang Loidl, Yue Che, Andreas Hiester, Cord Matthies, Martin Pichler, Pia Paffenholz, Luis Kluth, Mike Wenzel, Jörg Sommer, Julia Heinzelbecker, Philipp Schriefer, Alexander Winter, Friedemann Zengerling, Mario Wolfgang Kramer, Marie Lengert, Jana Frey, Axel Heidenreich, Christian Wülfing, Arlo Radtke, Klaus-Peter Dieckmann
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Surveillance of clinical stage I (CSI) testicular germ cell tumors (GCT) is hampered by low sensitivity and specificity of current biomarkers for detecting relapses. This study evaluated if serum levels of microRNA371a-3p (M371 test) can: (i) Accurately detect relapses, (ii) detect relapses earlier than conventional technology, and (iii) if elevated postoperative M371 levels may predict relapse. Experimental Design: In a multicentric setting, 258 patients with testicular CSI GCT were prospectively followed by surveillance for a median time of 18 months with serial measurements of serum M371 levels, in addition to standard diagnostic techniques. Diagnostic characteristics of M371 for detecting relapses were calculated using ROC curve analysis. Results: Thirty-nine patients recurred (15.1%), all with elevated M371 levels; eight without relapse had elevations, too. The test revealed the following characteristics: area under the ROC curve of 0.993, sensitivity 100%, specificity 96.3%, positive predictive value 83%, negative predictive value 100%. Earlier relapse detection with the test was found in 28%, with non-significant median time gain to diagnosis. Postoperative M371 levels did not predict future relapse. Conclusions: The sensitivity and specificity of the M371 test for detecting relapses in CSI GCTs are much superior to those of conventional diagnostics. However, post-orchiectomy M371 levels are not predictive of relapse, and there is no significant earlier relapse detection with the test. In all, there is clear evidence for the utility of the M371 test for relapse detection suggesting it may soon be ready for implementation into routine follow-up schedules for patients with testicular GCT.
Effectiveness of a fourth dose of COVID-19 mRNA vaccine in patients with systemic autoimmune rheumatic diseases using disease-modifying antirheumatic drugs: an emulated target trial
Authors: Jennifer S Hanberg, Xiaoqing Fu, Xiaosong Wang, Naomi J Patel, Yumeko Kawano, Abigail Schiff, Emily N Kowalski, Claire E Cook, Kathleen M M Vanni, Krishan Guzzo, Grace Qian, Katarina J Bade, Alene Saavedra, Rathnam Venkat, Shruthi Srivatsan, Yuqing Zhang, Jeffrey A Sparks, Zachary S Wallace
Journal: The Lancet Rheumatology (2023)
Regulation of Axon Degeneration after Injury and in Development by the Endogenous Calpain Inhibitor Calpastatin
Authors: Jing Yang, Robby M. Weimer, Dara Kallop, Olav Olsen, Zhuhao Wu, Nicolas Renier, Kunihiro Uryu, Marc Tessier-Lavigne
Journal: Neuron (2023)
Amyloid-Beta (Aβ) Plaques Promote Seeding and Spreading of Alpha-Synuclein and Tau in a Mouse Model of Lewy Body Disorders with Aβ Pathology
Authors: Fares Bassil, Hannah J. Brown, Shankar Pattabhiraman, Joe E. Iwasyk, Chantal M. Maghames, Emily S. Meymand, Timothy O. Cox, Dawn M. Riddle, Bin Zhang, John Q. Trojanowski, Virginia M.-Y. Lee
Journal: Neuron (2023)
Growth differentiation factor‐15 and the effect of empagliflozin in heart failure: Findings from the <scp>EMPEROR</scp> program
Authors: João Pedro Ferreira, Milton Packer, Javed Butler, Gerasimos Filippatos, Stuart J. Pocock, James L. Januzzi, Naveed Sattar, Sandra González Maldonado, Marina Panova‐Noeva, Mikhail Sumin, Serge Masson, Stefan D. Anker, Faiez Zannad
Journal: European Journal of Heart Failure (2023)

Growth differentiation factor-15 (GDF-15) is upregulated in part in response to cardiomyocyte stretch and stress, and it exerts a protective role that is mediated by its action to suppress signalling through insulin-like growth factor (IGF) and enhance signalling through adenosine monophosphate-activated protein kinase (AMPK). Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve outcomes in heart failure, which has been experimentally linked to AMPK. This study aimed at evaluating the associations of GDF-15 with baseline characteristics, the prognostic significance of GDF-15, and the effect of empagliflozin on GDF-15 in patients with heart failure with a reduced and preserved ejection fraction.
Cancer-Associated Thrombosis
Authors: Laurent Bertoletti, Olga Madridano, David Jiménez, Alfonso Muriel, Behnood Bikdeli, Cihan Ay, Javier Trujillo-Santos, Marijan Bosevski, Patricia Sigüenza, Manuel Monreal
Journal: JACC CardioOncology (2023)

Despite advances in cancer and venous thromboembolism (VTE) management, the epidemiology of cancer-associated thrombosis management over time remains unclear.
Decidual stromal cells for the treatment of severe COVID-19 ARDS
Authors: John Granton, Igor N. Novitzky-Basso, Alexandra Binnie, Jonas Mattsson, Michael Beyea, Mats Remberger, Clair Moura, Judy Lew, Cindy Yau, Anuj Singla, Hanne Scholz, Yngvar Fløisand, Lorenzo del Sorbo, Sanjay Mehta, Arthur Slutsky, John Laffey
Journal: Intensive Care Medicine (2023)
Characteristics and outcomes of immunotherapy-related liver injury in patients with hepatocellular carcinoma versus other advanced solid tumours
Authors: Ciro Celsa, Giuseppe Cabibbo, Claudia A.M. Fulgenzi, Bernhard Scheiner, Antonio D’Alessio, Giulia F. Manfredi, Naoshi Nishida, Celina Ang, Thomas U. Marron, Anwaar Saeed, Brooke Wietharn, Matthias Pinter, Jaekyung Cheon, Yi-Hsiang Huang, Pei-Chang Lee, Samuel Phen, Anuhya Gampa, Anjana Pillai, Caterina Vivaldi, Francesca Salani, Gianluca Masi, Natascha Roehlen, Robert Thimme, Arndt Vogel, Martin Schönlein, Johann von Felden, Kornelius Schulze, Henning Wege, Peter R. Galle, Masatoshi Kudo, Lorenza Rimassa, Amit G. Singal, Paul El Tomb, Susanna Ulahannan, Alessandro Parisi, Hong Jae Chon, Wei-Fan Hsu, Bernardo Stefanini, Elena Verzoni, Raffaele Giusti, Antonello Veccia, Annamaria Catino, Giuseppe Aprile, Pamela Francesca Guglielmini, Marilena Di Napoli, Paola Ermacora, Lorenzo Antonuzzo, Ernesto Rossi, Francesco Verderame, Fable Zustovich, Corrado Ficorella, Francesca Romana Di Pietro, Nicola Battelli, Giorgia Negrini, Francesco Grossi, Roberto Bordonaro, Stefania Pipitone, Maria Banzi, Serena Ricciardi, Letizia Laera, Antonio Russo, Ugo De Giorgi, Luigi Cavanna, Mariella Sorarù, Vincenzo Montesarchio, Paola Bordi, Leonardo Brunetti, Carmine Pinto, Melissa Bersanelli, Calogero Cammà, Alessio Cortellini, David J. Pinato
Journal: Journal of Hepatology (2023)

Immune-related liver injury (irLI) is commonly observed in patients with cancer treated with immune checkpoint inhibitors (ICIs). We aimed to compare the incidence, clinical characteristics, and outcomes of irLI between patients receiving ICIs for hepatocellular carcinoma (HCC) vs. other solid tumours.
Evaluation of Neural Regulation and Microglial Responses to Brain Injury in Larval Zebrafish Exposed to Perfluorooctane Sulfonate
Authors: Shannon E. Paquette, Nathan R. Martin, April Rodd, Katherine E. Manz, Eden Allen, Manuel Camarillo, Hannah I. Weller, Kurt Pennell, Jessica S. Plavicki
Journal: Environmental Health Perspectives (2023)

Per- and polyfluoroalkyl substances (PFAS) are biopersistent, global pollutants. Although some in vitro and epidemiological studies have explored the neurotoxic potential of perfluorooctane sulfonate (PFOS), a prevalent PFAS congener, it is unknown how developmental PFOS exposure affects neuronal signaling, microglia development, and microglial–neuron communication.
Transforming Team Performance Through Reimplementation of the Surgical Safety Checklist
Authors: James C. Etheridge, Rachel Moyal-Smith, Tze Tein Yong, Shu Rong Lim, Yves Sonnay, Christine Lim, Hiang Khoon Tan, Mary E. Brindle, Joaquim M. Havens
Journal: JAMA Surgery (2023)

Patient safety interventions, like the World Health Organization Surgical Safety Checklist, require effective implementation strategies to achieve meaningful results. Institutions with underperforming checklists require evidence-based guidance for reimplementing these practices to maximize their impact on patient safety.